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Purpose: Neoadjuvant radiotherapy (RT) or chemoradiotherapy (CRT) is the standard treatment for locally advanced rectal adenocarcinoma. The recent emerging data on preoperative immunotherapy as an effective therapeutic modality for mismatch repair deficient rectal carcinomas suggests that the immune system plays a significant role in tumor eradication. Although RT has been shown to stimulate anti-tumor immunity, it also leads to substantial lymphopenia, hindering the effect of immune response. Materials and Methods: We retrospectively analyzed 33 rectal adenocarcinoma patients who underwent CRT in our department, aiming to identify the effects of CRT on the peripheral blood lymphocyte counts (LC) and the potential impact of CRT-induced lymphopenia on tumor response and prognosis of patients. Results: A statistically significant decrease in the LC of patients was observed after CRT (median values of 2,184/μL and 517/μL before and after treatment, respectively; p < 0.001). While no correlation between ypT-stage, ypN status, and LC was found, poor tumor regression grade was significantly associated with lower LC (p = 0.036). Moreover, lymphopenia was associated with poorer distant metastasis- free survival (p = 0.003). Distant metastases were documented in 0% of patients with post- CRT LC above 518/μL vs. 44.5% of patients with lower LC values. Conclusion: Although further investigation is demanded, given the limited number of patients analyzed in the study, lymphopenia emerges as a significant adverse event that rectal adenocarcinoma patients face during treatment with neoadjuvant CRT, with subsequent implications on tumor response and prognosis. Protection of the immune system during CRT emerges as an important target for clinical research. [ABSTRACT FROM AUTHOR]